Molecular and functional interactions between tumor necrosis factor-alpha receptors and the glutamatergic system in the mouse hippocampus: Implications for seizure susceptibility

Abstract

Abstract-Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine acting on two distinct receptor subtypes, namely p55 and p75 receptors. TNF-alpha p55 and p75 receptor knockout mice were previously shown to display a decreased or enhanced susceptibility to seizures, respectively, suggesting intrinsic modifications in neuronal excitability. We investigated whether alterations in glutamate system function occur in these naive knockout mice with perturbed cytokine signaling that could explain their different propensity to develop seizures. Using Western blot analysis of hippocampal homogenates, we found that p55 ؊/؊ mice have decreased levels of membrane GluR3 and NR1 glutamate receptor subunits while GluR1, GluR2, GluR6/7 and NR2A/B were unchanged as compared to wild-type mice. In p75 ؊/؊ mice, GluR2, GluR3, GluR6/7 and NR2A/B glutamate receptor subunits were increased in the hippocampus while GluR1 and NR1 did not change. Extracellular single-cell recordings of the electrical activity of hippocampal neurons were carried out in anesthetized mice by standard electrophysiological techniques. Microiontophoretic application of glutamate increased the basal firing rate of hippocampal neurons in p75 ؊/؊ mice versus wild-type mice, and this effect was blocked by 2-amino-5-phosphopentanoic acid and 6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione denoting the involvement of N-methyl-D-aspartic acid and AMPA receptors. In p55؊/؊ mice, hippocampal neurons responses to glutamate were similar to wild-type mice. Spontaneous glutamate release measured by in vivo hippocampal microdialysis was significantly decreased only in p55 ؊/؊ mice. No changes were observed in KCl-induced glutamate release in both receptor knockout mice strains versus wild-type mice. These findings highlight specific molecular and functional interactions between p55 and p75 receptor-mediated signaling and the glutamate system. These interactions may be relevant for controlling neuronal excitability in physiological and pathological conditions.

TNF-Overexpression in Borna Disease Virus-Infected Mouse Brains Triggers Inflammatory Reaction and Epileptic Seizures

“…presensitation for epileptic seizures, host immune response, reaction pattern of brain cells and viral spread in the CNS. Intriguing actions of TNF in the CNS range from induction of antiviral immune responses, proconvulsive and anticonvulsive effects up to neurodegenerative and neuroprotective properties [1]–[6], [10], [20], [42], [43], [47], [52]–[54]. Thus, a biological effect on BDV-infection could be anticipated.…”

Inflammation in epileptogenesis after traumatic brain injury

“…Cytokines have been found to inhibit the uptake of glutamate by astrocytes in culture [94] and modulate excitatory neurotransmission in the brain through NMDA and alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propoinate (AMPA) receptors [95, 96]. For example, IL-1β produced by microglia can enhance NMDA-mediated Ca 2+ currents through cell surface type 1 IL-1R (IL-1R1) co-localized on pyramidal cell dendrites [89].…”

“…For example, IL-1β produced by microglia can enhance NMDA-mediated Ca 2+ currents through cell surface type 1 IL-1R (IL-1R1) co-localized on pyramidal cell dendrites [89]. Pre-synaptic NMDA receptors are agonists for Ca 2+ -mediated glutamate release, and when activated by inflammatory factors such as IL-1β and HMGB1 can cause an excess of intracellular Ca 2+ leading to an extracellular hyperexcitability and excitotoxicity [95]. Several other cytokines including TNF-α and IL-10 have also been associated with the regulation of seizure duration in experimental kindling models [97, 98].…”

Immunity and Inflammation in Epilepsy

“…IL-1b, TNF-a, and IL-6 and prostaglandins, such as PGE2 and PGF2a, modify voltage-and receptor-gated ion channel function via rapid activation of posttranslational mechanisms in neurons involving protein kinases (Viviani et al 2007;Kulkarni and Dhir 2009;Vezzani et al 2013b). Cytokines also promote changes in neuronal glutamate (N-methyl-D-aspartate [NMDA] and AMPA) and g-aminobutyric acid (GABA) A receptor expression, and alter their molecular subunit composition by activating protein kinases (Stellwagen et al 2005;Balosso et al 2009). Cytokines may increase neuronal excitability also by inducing transcriptional down-regulation of glutamate transporter GLT-1 in astrocytes, and by promoting astrocytic release of ATP, glutamate, glycine, and D-serine, which, in turn, activate their neuronal receptors and enhance glutamatergic transmission (Devinsky et al 2013).…”